Neoadjuvant treatment of breast cancer

ABSTRACT

Neoadjuvant treatment of inflammatory or T3 to T4 breast cancer is carried out by administering to such patients a number of cycles of chemotherapy treatment in which DPPE first is administered followed by a combination of anthracyclines and taxanes.

FIELD OF THE INVENTION

The present invention relates to the treatment of breast cancer.

BACKGROUND OF THE INVENTION

One of the major chemotherapeutic treatments is that of malignant growth(cancer) in humans. The objective of chemotherapy is the totalextermination of clonogenic tumor or malignant cells, with minimaldamage to the patient. However, one of the major limitations of thechemotherapeutic approach for managing human cancer is the generalinability of anticancer drugs to discriminate between normal andtumorous cells. Anti-neoplastic agents have the lowest therapeuticindicies of any class of drugs used in humans and hence producesignificant and potentially life-threatening toxicities. Certaincommonly-used anti-neoplastic agents have unique and acute toxicitiesfor specific tissues. For example, the vinca alkaloids possesssignificant toxicity for nervous tissues, while adriamycin has specifictoxicity for heart tissue and bleomycin has for lung tissue. In general,almost all members of the major categories of anti-neoplastic agentshave considerable toxicities for normal cells of gastrointestinal,epidermal and myelopoietic tissues.

Generally, the dose-limiting consideration for chemical management ofcancer in humans is the toxicity that anti-neoplastic agents have forthe pluripotent stem cells of myelopoietic tissue. This toxicity arisesfrom the fact that most anticancer drugs function preferentially againstproliferating cells but with no significant capacity to discriminatebetween cycling normal and cycling tumor tissues.

In certain types of locally-advanced breast cancer, specificallyinflammatory or T3 to T4 breast cancer, there is applied a treatmentwith chemotherapeutic agents prior to surgical removal of the tumor, inorder to reduce the size of tumor. T3 tumors are tumors sized >3 and <4cm. T3 tumors may be operable or inoperable depending on where in thebreast they are located. For example, they are often inoperable if closeto the chest wall, especially in small breasts. T4 tumors are tumorssized >4 cm and generally are inoperable. Inflammatory breast cancerinfiltrates the lymphatics of the skin, is usually a diffuse tumor andvery high grade in term of malignancy.

In U.S. Pat. Nos. 6,288,799, 5,859,065, 5,708,329, 5,747,543 and5,618,846, all assigned to University of Manitoba and the disclosures ofwhich are incorporated herein by reference, there is described animproved method for the in vivo chemotherapeutic treatment of cancer inwhich there is first administered a compound which inhibits normal cellproliferation while promoting malignant cell proliferation, specificallya potent antagonist selective for intracellular histamine receptors, inan amount sufficient to inhibit the binding of intracellular histamineto the receptors in normal and malignant cells. Following sufficienttime to permit the inhibition of binding of intracellular histamine, achemotherapeutic agent is administered. An enhanced toxic effect on thecancer cells from the chemotherapeutic agent is obtained while anyadverse effect of the chemotherapeutic agent on normal cells,particularly bone marrow and gastrointestinal cells, is significantlyameliorated. One useful compound which inhibits normal cellproliferation while promoting malignant cell proliferation isN,N-diethyl-2-[4-(phenylmethyl)-phenoxy]ethanamine, abbreviated hereinas DPPE.

SUMMARY OF INVENTION

It has now surprisingly been found, in a Phase II clinical trial, theprocedure described in the aforementioned patents when using acombination of an anthracycline chemotherapeutic agent and a taxanetherapeutic agent is an effective procedure in neoadjuvant treatment ofinflammatory breast cancer or T3 to T4 breast cancer. In addition, theprocedure leads to long term survival post surgery.

Accordingly, in one aspect, the present invention provides a method ofneoadjuvant chemotherapy in patients with inflammatory or T3 to T4breast cancer, which comprises administering to said patients aplurality of cycles of chemotherapy at predetermined intervals untilcancerous tissue is reduced to an operable size or is in remission,wherein each said cycle comprises:

(a) first administering to said patients at least one diphenyl compoundof the formula:

wherein X and Y are each fluorine, chlorine or bromine, Z is an alkylenegroup of 1 to 3 carbon atoms or ═C═O, or the phenyl groups are joined toform a tricyclic ring, o and p are 0 or 1, R₁ and R₂ are each an alkylgroup containing 1 to 3 carbon atoms or are joined together to form aheterocyclic ring with the nitrogen atom and n is 1, 2 or 3, orpharmaceutically-acceptable salts thereof, and

(b) following sufficient time to permit inhibition of binding ofintracellular histamine, subsequently administering to the patient ananthracycline chemotherapeutic agent and a taxane chemotherapeuticagent.

In the application of the present invention, the diphenyl compound andthe chemotherapeutic agents are generally administered by intravenousinfusion. In one preferred procedure, a solution of the diphenylcompound is administered to the patient over a desired period of timeprior to administration of the chemotherapeutic agents and a solution ofthe chemotherapeutic agents in combination with the diphenyl compoundthen is administered for the period of administration of thechemotherapeutic agents. If desired, a solution of the diphenyl compoundis administered after completion of the administration of thechemotherapeutic agents for a desired period of time to ameliorate sideeffects from the administration of the chemotherapeutic agents.

GENERAL DESCRIPTION OF INVENTION

In the present invention, a diphenyl compound is used which is a potentantagonist of histamine binding at the intracellular histamine receptorand is administered in an amount sufficient to inhibit the binding ofintracellular histamine at the intracellular binding site (Hic) innormal cells. Such compounds exhibit a pKi of at least about 5,preferably at least about 5.5.

Specific potent compounds which are useful in the present invention arediphenyl compounds of the formula:

wherein X and Y are each fluorine, chlorine or bromine, Z is an alkylenegroup of 1 to 3 carbon atoms or ═C═O, o and p are 0 or 1, R₁ and R₂ areeach alkyl groups containing 1 to 3 carbon atoms or are joined togetherto form a hetero-ring with the nitrogen atom and n is 1, 2 or 3.Pharmaceutically-acceptable salts of the diphenyl compounds may beemployed.

Alternatively, the benzene rings may be joined to form a tricyclic ring,in accordance with the structure:

In one preferred embodiment, the group

is a diethylamino group, although other alkylamino groups may beemployed, such as dimethylamino, and, in another preferred embodiment, amorpholino group, although other heterocyclic ring groups may beemployed, such as piperazino. o and p are usually 0 when Z is analkylene group and n may be 2. In one particularly preferred embodiment,Z is —CH₂—, n is 2, o and p are each 0 and

is a diethylamino group. This compound, namelyN,N-diethyl-2-[4-(phenylmethyl)-phenoxy]ethanamine, which may be in theform of the free base or in the form of its hydrochloride or otherpharmaceutically-acceptable salt, is abbreviated herein as DPPE. Inaddition to a methylene group linking the benzene rings, other linkinggroups may be employed, such as ═C═O. Other substitutents may beprovided on the benzene rings in addition to the halogen atoms, forexample, an imidazole group.

The diphenyl compound employed in the present invention is administeredto the patient in any convenient manner, such as by intravenousinjection of a solution thereof in an aqueouspharmaceutically-acceptable vehicle. The diphenyl compound isadministered to the patient over a period of time before administrationof the chemotherapeutic agents.

The chemotherapeutic agents employed herein are anthracyclines,preferably doxorubicin and epirubicin; and taxanes, preferably Taxol(Trademark of Bristol-Myers Squibb for paclitaxel) and Taxotere(Trademark of Aventis Pharma for docetaxel). The mixture ofchemotherapeutic agents is administered in any manner consistent withtheir normal manner of administration in conventional breast cancertherapy, usually by intravenous infusion of a solution thereof.

The administration of the diphenyl compound to the patient prior toadministration of the chemotherapeutic agents is necessary in order topermit the diphenyl compound to inhibit the binding of intracellularhistamine in normal and malignant cells and thereby, in effect, shutdown the proliferation of the normal cells, but increase proliferationof malignant cells.

The length of time prior to administration of the chemotherapeuticagents that the diphenyl compound is administered depends on thediphenyl compound, its mode of administration and the size of thepatient. Generally, the diphenyl compound is administered to the patientfor about 30 to about 90 minutes, preferably about 60 minutes, prior toadministration of the chemotherapeutic agents.

The quantity of diphenyl compound administered to the patient depends onthe side effects to be ameliorated, but should be at least sufficient toinhibit binding of intracellular histamine in normal cells. The quantityrequired to achieve the beneficial effects of the present inventiondepends upon the diphenyl compound employed, the chemotherapeutic agentsemployed and the quantity of such agents employed.

In general, the quantity of diphenyl compound employed in humans is fromabout 8 to about 320 mg/M² of human to which the diphenyl compound isadministered, with about 8 and 240 mg/M² being the optimal dose forgastro-intestinal and bone marrow protection, respectively. Over thisdose range, the present invention is able to achieve an enhancedchemotherapeutic effect on breast cancer cells while, at the same time,also protecting normal cells from damage by the chemotherapeutic agentsin a wide variety of circumstances where traditional chemotherapy leadsto damage of normal cells or tissues not involved in the diseaseprocess.

In the neoadjuvant treatment of inflammatory or T3 to T4 breast cancer,the diphenyl compound preferably is used in an amount of about 3 toabout 10 mg/kg of patient, administered intravenously over a period ofabout 30 to about 90 minutes prior to administration of thechemotherapeutic agents and continuing for the period of administrationof the chemotherapy agent. In the specific Phase II clinical trialdescribed herein, there was employed 6 mg/kg of DPPE in the form of itshydrochloride salt, administered intravenously as an aqueous solutionthereof over 80 minutes, with the last twenty minutes being accompaniedby infusion of the chemotherapeutic agents, followed by the intravenousadministration of an aqueous solution at a dose of 2.5 mg/kg of DPPE for180 minutes accompanied by the infusion of Taxol or for 60 minutesaccompanied by the infusion of Taxotere.

A second regimen for DPPE/Taxotere treatment is the intravenousadministration of an aqueous solution of DPPE for 80 minutes, with thelast 20 minutes being accompanied by infusion of the Taxotere, followedby infusion of Taxotere alone for 40 minutes.

The chemotherapy agents which are employed herein preferably are used ina total amount of 75 to about 225 mg/M² of patient consistent with theidentity of the chemotherapy agent. The chemotherapeutic agents may beadministered in an amount of about 50 to about 60 mg/M² of patient fordoxorubicin or epirubicin, about 175 to about 225 mg/M² of Taxol andabout 75 to about 100 mg/M² of Taxotere. In the specific Phase IIclinical trial described herein, there was employed 50 mg/M² ofdoxorubicin or epirubicin, and 175 mg/M² of Taxol or 75 mg/M² ofTaxotere, administered over the last 20 minutes of infusion of the DPPEsolution and over a further 180 minutes for Taxol or 60 minutes forTaxotere, accompanied by infusion of a 2.5 mg/kg of DPPE solution.

As noted above, patients with inflammatory breast cancer or T3 to T4breast cancer are subjected to a number of cycles of chemotherapy atpredetermined intervals to reduce the size of the tumor to an operablesize. The number of cycles for each patient is generally about 5 toabout 8 cycles, with about 21 to about 28 days between each cycle. Inthe Phase II clinical trial, patients were subjected to 6 cycles at timeintervals of 21 days.

As set forth herein, a Phase II clinical trial was conducted on patientshaving inflammatory or T3 to T4 breast cancer in which patients wereadministered DPPE followed by doxorubicin or epirubicin and Taxol orTaxotere. Various data from the clinical trial were collected andanalyzed.

The results of this trial showed that DPPE along withdoxorubicin/epirubicin and Taxol/Taxotere was an effective neoadjuvanttreatment which lead to long term survival post surgery.

EXAMPLE

This Example illustrates the neoadjuvant treatment of inflammatory orT3-T4 breast cancer.

A Phase II clinical trial was carried out in which patients (N=8) withinflammatory (N=7) and T3 to T4 (N=1) breast cancer were treated with acombination of DPPE and epirubicin (EPI)/Taxol (N=5), a combination ofDPPE and doxorubicin (DOX)/Taxol (N=2) and DPPE and a combination ofDPPE and epirubicin/axotere (N=1). DPPE was administered at a dose of 6mg/M² over 80 minutes with a combination of epirubicin or doxorubicin ata dose of 50 mg/M² and Taxol at a dose of 175 mg/M² or Taxotere at adose of 75 mg/M² over the last 20 minutes and during a further 180minutes for Taxol or 60 minutes for Taxotere, at a dose of 2.5 mg/kg.The treatment was repeated at 21 day intervals for 6 cycles. The eightpatients with inflammatory or T3 to T4 breast cancer had no previouschemo- or radiotherapy. When the chemotherapy cycles were complete, thecancerous tissue was removed and the patients observed.

The results obtained are shown in Table, I. In this Table, theabbreviation TTP stands for time to progression and the abbreviation OSstands for overall survival. Two long-term survivors (45+ and 53+months) had mixed high-grade tumors pre-treatment but no high-gradecomponent post-surgery. A third patient with only high-grade cells orcytology, had a clinical/pathological complete remission. This patientremains disease-free at 55+months.

These findings are compatible with the hypothesis advanced in copendingU.S. Applications No. 60/331,242 filed Nov. 9, 2001 and No. ______ filed______, the disclosures of which are incorporated herein by reference(WO ______), in the names of Lorne Brandes and Mark Vincent, thatDPPE-based chemotherapy may preferentially target high-grade malignantcell populations.

1. A method of neoadjuvant chemotherapy in patients with inflammatorybreast cancer or T3 or T4 breast cancer which comprises administering tosaid patient a plurality of cycles of chemotherapy at predeterminedintervals until cancerous tissue is reduced to an operable size or is inremission, wherein each said cycle comprises: (a) first administering tosaid patients at least one diphenyl compound of the formula:

wherein X and Y are each fluorine, chlorine or bromine, Z is an alkylenegroup of 1 to 3 carbon atoms or ═C═O, or the phenyl groups are joined toform a tricyclic ring, o and p are 0 or 1, R₁ and R₂ are each an alkylgroup containing 1 to 3 carbon atoms or are joined together to form aheterocyclic ring with the nitrogen atom and n is 1, 2 or 3, orpharmaceutically-acceptable salts thereof, and (b) following sufficienttime to permit inhibition of binding of intracellular histamine,subsequently administering to the patient an anthracyclinechemotherapeutic agent and a taxane chemotherapeutic agent.
 2. Themethod of claim 1 wherein the group

is a diethylamino group, a dimethylamino group, a morpholino group or apiperazino group.
 3. The method of claim 1 wherein the group

is a diethylamino group, Z is —CH₂, n is 2 and o and p are each
 0. 4.The method of claim 3 wherein diphenyl compound is in the form of ahydrochloride salt.
 5. The method of claim 1 wherein said anthracyclinechemotherapeutic agent is doxorubicin or epirubicin.
 6. The method ofclaim 4 wherein said anthracycline chemotherapeutic agent is doxorubicinor epirubicin.
 7. The method of claim 1 wherein said taxanechemotherapeutic agent is Taxol or Taxotere.
 8. The method of claim 1wherein said diphenyl compound is administered to the patient about 30to about 90 minutes prior to said administration of saidchemotherapeutic agents.
 9. The method of claim 8 wherein said time isabout 60 minutes.
 10. The method of claim 7 wherein said diphenylcompound is administered by intravenous infusion of a solution thereofover a period of time of up to about 90 minutes prior to administrationof said chemotherapeutic agents and is maintained during administrationof said chemotherapeutic agents.
 11. The method of claim 10 wherein saiddiphenyl compound is administered for about 60 minutes prior toadministration of said chemotherapeutic agents and is maintained duringintravenous infusion of said chemotherapeutic agents.
 12. The method ofclaim 11 wherein administration of taxane chemotherapeutic agent,optionally in combination with anthracycline chemotherapeutic agent, iseffected during about 20 minutes maintenance of infusion of diphenylcompound, followed by continued infusion of diphenyl compound for theremainder of the administration of the taxane chemotherapeutic agent.13. The method of claim 8 wherein said diphenyl compound is administeredin an amount of about 8 to about 240 mg/M² of said patient.
 14. Themethod of claim 13 wherein said amount is about 3 to about 10 mg/kg ofpatient.
 15. The method of claim 10 wherein said diphenyl compound isadministered in an amount of about 3 to about 10 mg/kg of patient. 16.The method of claim 11 wherein said diphenyl compound is administered inan amount of about 6 mg/kg.
 17. The method of claim 16 wherein saidchemotherapeutic agents are administered in an amount of about 50 toabout 60 mg/M² of patient for doxorubicin or epirubicin, about 175 toabout 225 mg/M² for Taxol and about 75 to about 100 mg/M² of Taxotere.18. The method of claim 16 wherein said anthracycline chemotherapeuticagent is doxorubicin or epirubicin administered in an amount of 50 mg/M²and said taxane therapeutic agent is Taxol administered in an amount of175 mg/M² or Taxotere is administered in an amount of 75 mg/M².
 19. Themethod of claim 1 wherein the number of cycles of chemotherapy treatmentis about 5 to about 10 administered at intervals of about 21 to about 28days.